The mechanisms that regulate unrelenting pulmonary fibrosis are incompletely understood. Pulmonary fibrosis can occur in patients with chronic inflammatory diseases such as those associated with connective tissue diseases such as scleroderma, rheumatoid arthritis and polymyositis. Pulmonary fibrosis also occurs in diseases that are not characterized by the same degree of interstitial inflammation such as idiopathic pulmonary fibrosis. We have a identified a novel model system that appears to have a unique role in regulating the lung response to acute non-infectious injury as well as the subsequent inflammatory and fibroproliferative responses. Our preliminary studies have provided evidence that CXCR3 and the cognate chemokine ligand CXCL10 regulates three fundamental aspects of lung injury, inflammation and fibroproliferation: epithelial repair, development of profibrotic alternatively activated (M2) macrophages, and trafficking of fibroblasts to the lung. CXCR3 null mice suffer from progressive fibrosis after acute lung injury. Mice that overexpress CXCL10 in the lung are remarkably resistant to acute lung injury. We propose to determine the mechanisms by which the CXCL10-CXCR3 axis regulates lung repair, inflammation and fibrosis following lung injury in the following specific aims: 1. Determine the mechanisms by which the CXCL10/CXCR3 axis stimulates lung repair following non- infectious lung injury by the recruitment and expansion of progenitor epithelial cells. 2. Characterize the mechanisms by which CXCL10 regulates fibroblast recruitment to the lung through interactions with the proteoglycan syndecan-4. 3. Investigate the mechanisms by which CXCL10-CXCR3 interactions inhibit fibrogenesis by regulating the development of the alternatively activated macrophage phenotype. PUBLIC HEALTH RELEVANCE: This is a competitive renewal of a proposal that focuses on the role of the chemokine CXCL12 and its cognate receptor CXCR3 in the pathobiology of lung injury, inflammation and fibrosis. We have found that CXCL10 and CXCR3 are critical regulators of lung injury and repair in response to non-infectious lung injury through effects on lung epithelial cell repair, fibroblast recruitment to the lung and the development of alternatively activated macrophages. Understanding the roles of the CXCL10/CXCR3 axis in the pathobiology of lung injury and repair could lead to new therapies for progressive pulmonary fibrosis.